Biology subjects

Steglich, A.

Publications and source records attributed to Steglich, A..

3 recordsLinked to original sources

bioRxiv2026

Spatiotemporal Mapping of Glomerular Endothelial Regeneration Identifies Apold1 as an Intrinsic Regulator of Repair

Abstract Endothelial cell (EC) injury is central to the pathogenesis of various renal disorders, highlighting the critical importance of vascular repair for restoring organ health. However, due to limited access to human tissue during active regeneration, the exact reparative processes remain largely unknown. This study aimed to investigate regeneration mechanisms specifically within the glomerular microvasculature by utilizing a selective endothelial cell injury (ECI) model in mice.Lineage tracing identified the origin of regenerating ECs. To uncover the transcriptional dynamics driving these reparative changes, we combined single-cell RNA sequencing and Xenium spatial transcriptomics (ST), mapping distinct glomerular EC (gEC) subpopulations across different phases of injury and recovery. Apold1 emerged as a key regulatory candidate within this process. To functionally validate this gene's specific role during the regenerative phase, Apold1-deficient (Apold1-/-) mice underwent the ECI model. After showing that gECs regenerate primarily from local, pre-existing renal ECs, our transcriptomic analysis identified 10 distinct gEC subpopulations and revealed a complex temporal pattern of regeneration. This process begins with the expression of genes associated with inflammation, followed sequentially by endothelial cell (EC) migration, the activation of immediate early genes, vascular remodeling and cellular proliferation. Within this dynamic process, the EC-specific gene Apold1 was identified as a key regulatory candidate. Apold1-/- mice exhibited impaired endothelial regeneration, characterized by increased endothelial activation and greater immune cell infiltration seven days post-ECI. To our knowledge, this is the first study to elucidate the spatiotemporal mechanisms of glomerular endothelial cell regeneration. By identifying local gECs as the primary source of repair, and stablishing the change in their expression pattern during regeneration, as well as identifying Apold1 as an intrinsic regulator, we have laid the groundwork for future research on renal microvascular disorders.

molecular biology↗

bioRxiv2026

Empagliflozin preserves mitochondrial function and reduces tubular injury in obese type 2 diabetic ZSF-1 rats

Diabetic nephropathy remains the leading cause of end-stage renal disease. The ZSF-1 rat model combines features known as the metabolic syndrome, such as type 2 diabetes mellitus, hypertension and obesity, developing progressive kidney disease. In this study, we investigated the nephroprotective mechanisms of the SGLT2 inhibitor empagliflozin, focusing on mitochondrial function. Obese ZSF-1 rats were randomized at 24 weeks of age to receive either placebo or empagliflozin for eight weeks, while lean ZSF-1 rats served as healthy controls. Kidney function, assessed by glomerular filtration rate (GFR), was significantly reduced in obese rats and was not improved by empagliflozin treatment. However, obese animals exhibited increased tubular injury, tubular cast formation, and elevated total and tubular proteinuria, all of which were attenuated by empagliflozin. Mitochondrial function was evaluated in freshly isolated cortical kidney mitochondria by measuring oxygen consumption. Obese ZSF-1 rats showed impaired respiratory capacity and reduced protein expression of oxidative phosphorylation (OXPHOS) complexes II, III, IV, and V, indicating mitochondrial dysfunction. Empagliflozin treatment improved mitochondrial function by enhancing complex I- and IV-linked respiration and restoring the expression of OXPHOS complexes II, III, and IV. In addition, empagliflozin treatment was linked to improved mitochondrial dynamics and modulation of autophagic activity, suggesting enhanced mitochondrial quality control. Overall, these findings demonstrate that empagliflozin exerts nephroprotective effects primarily at the tubular level in obese ZSF-1 rats. The beneficial effects appear to be mediated through improved mitochondrial function, enhanced mitochondrial integrity, and reduced tubular injury.

physiology↗

bioRxiv2026

Renin is critical for Renin Lineage Cell Plasticity and Migration in experimental crescentic Glomerulonephritis

Key PointsO_LIRenin deficiency in renin-lineage cells worsened crescentic injury and impaired cell migration, revealing a protective role for renin in crescentic glomerulonephritis. C_LIO_LILoss of renin shifted renin-lineage cells signaling toward interferon/STAT1-driven C_LIO_LIRenin-lineage cell ablation in crescentic glomerulonephritis induced a less inflammatory disease time-course. C_LI BackgroundThe adult juxtaglomerular renin-lineage cell (RLC) niche contributes to intraglomerular repair after injury, but their role in highly inflammatory crescentic glomerulonephritis (cGN) remains unclear. While angiotensin II-AT1R signaling promotes fibrosis and inflammation, the contribution of the RLCs, and of renin expression within RLCs, to cGN outcome has not been investigated. MethodsWe used tdTomato lineage-tracing to track RLCs in wild-type (WT) and renin-knockout (RenKO) mice following cGN induction. RLC migration and glomerular injury were quantified histologically. Single-cell RNA sequencing was performed on isolated tdTomato-positive cells at day 10 and 21 after injury to characterize transcriptional programs. Disease progression was additionally examined in mice with diphtheria toxin A-mediated (DTA) RLC ablation. ResultsRLCs were detected within injured glomeruli during cGN, with sporadic localization to crescentic lesions. Genetic renin deletion in RLCs worsened cGN outcomes, with RenKO mice developing increased albuminuria (by 306%), crescent formation (by 50%) and podocyte loss (by 15%) by day 21 compared to WT controls. Renin-deficient RLCs exhibited a reduced intraglomerular migratory response with decreased colocalization with mesangial and podocytes cell markers. Single-cell transcriptomic analysis supports an immunomodulatory reparative phenotype in WT RLCs. In contrast, RenKO RLCs displayed enrichment of interferon-stimulated genes and pathways suppressing cell migration. RLC ablation reduced macrophage infiltration, but did not alter disease progression, suggesting compensatory cellular mechanisms. ConclusionsRenin expression supports the plasticity and injury-associated responses of RLCs during cGN. Loss of renin shifts RLCs toward an interferon-driven inflammatory and antimigratory phenotype that aggravates glomerular injury, while ablation of the RLCs may be compensated without major outcome changes.

pathology↗